The broad goal of this project is to define the mechanisms of menopause-associated insomnia and depression in order to improve therapeutic approaches to these common and debilitating disorders. Women are at increased risk for insomnia and depression during the perimenopause and early postmenopause. Hot flashes have been linked to menopause-associated insomnia and depression, but the biological basis of these associations is poorly understood. This proposal will explore the basis for the association between hot flashes and depression to determine if hot flashes are associated with depression: (1) because hot flashes are merely a marker for menopause-associated alterations in gonadal hormones, and/or (2) because hot flashes exert their effects on depression through their sleep-disrupting effects. In this proposal, we will dissect the complex interactions among gonadal hormones and menopausal symptoms in women using an experimental model of hot flashes in premenopausal women (Aims 1 and 2) and a clinical intervention study in postmenopausal women (Aim 3). Aim 1 will determine the effect of hot flashes on sleep to test the hypotheses that hot flashes worsen objectively measured sleep and lead to the perception of poor sleep quality over time. Aim 2 will identify the relative effects of hot flashes and sleep disruption on mood. This will test the hypotheses that objectively measured sleep disturbance has a greater effect than hot flashes on mood and that perception of poor sleep correlates with negative mood. Aim 3 will define the relative effects of hot flashes and changes in estradiol on mood. This will test the hypotheses that estrogen treatment has a similar therapeutic effect on mood in women with and without hot flashes and that increasing levels of estradiol correlate with improvement in mood. The significance of these findings lies in their ability to define the causal contributions of gonadal hormone changes, hot flashes and sleep disruption to menopause-associated mood disturbance. Since the results of the Women's Health Initiative described important risks of hormone therapy, fewer women are being treated with hormone therapy. Similarly, although serotonergic reuptake inhibitors are effective antidepressants and suppress hot flashes in some women, their side effect profiles may limit their acceptability. Novel treatment approaches are needed. Understanding the causal pathways between alterations in gonadal hormones, hot flashes, sleep disruption, and mood disturbance will inform the development of rational and targeted therapeutic strategies for management of menopause-associated depression. PUBLIC HEALTH RELEVANCE: This study will identify the mechanisms of menopause-associated insomnia and depression, common and debilitating disorders for which women are at increased risk during midlife. The proposed mechanistic studies will define the impact of hot flashes on sleep and the relative effects of gonadal hormones, hot flashes, and sleep disruption on mood disturbance. This work has important public health relevance because it will inform the development of rational therapeutic strategies and lead to novel treatment paradigms for menopause- associated depression.